Combined aerobic and strength exercise training on biological ageing in Singaporean breast cancer patients: protocol for the Breast Cancer Exercise Intervention (BREXINT) Pilot Study.

Breast cancer (BC) is the most prominent cancer amongst women, but fortunately, early diagnosis and advances in multimodality treatments have improved patient survivability. Cancer survivors, however, experience increased biological ageing which may accelerate other co-morbidities. Exercise intervention is a promising clinical adjuvant approach to improve BC patients' physiological function, recovery from treatment, and quality of life. However, the effects of combined aerobic and strength exercise training on biological ageing in BC patients have not been studied. The Breast Cancer Exercise Intervention (BREXINT) Pilot Study will evaluate the effects of a 24-week combined aerobic and strength exercise intervention against usual care in 50 BC patients' post-treatment randomised to either group. The primary outcomes include changes in cardiorespiratory fitness, muscle strength, cancer-related symptoms, and rate of biological ageing following exercise intervention period. The secondary outcomes include habitual physical activity measured with tri-axial accelerometery and supporting questionnaires, including physical activity, food diary, and quality of life questionnaires. This study will identify the effects of combined aerobic exercise strength training on biological ageing in BC patients from Singapore. Results from this study could further support the implementation of regular exercise programmes as routine care for cancer patients.

The cardioprotective potential of sodium-glucose cotransporter 2-inhibitors in breast cancer therapy-related cardiac dysfunction - A systematic review.

BACKGROUND: Sodium-glucose cotransporter 2-inhibitors (SGLT2i) improve cardiovascular outcomes including reduction in risk of first hospitalisation for heart failure (HF), worsening HF and cardiovascular death regardless of HF or diabetes mellitus (DM) status. It is not known whether SGLT2i can prevent the development of incident HF or reduce the risk of HF in patients receiving trastuzumab with or without other concurrent anti-HER2 agent or sequential anthracycline for treatment of HER2 positive breast cancer. Patients with active malignancy or recent history of malignancy were excluded from participating in the main cardiovascular outcome trials involving SGLT2i. AIM: A systematic review was performed to objectively assess published literature on the cardioprotective effects of SGLT2i in breast cancer treatment-related cardiotoxicity. METHODS: Systematic searches of Embase, Medline, The Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases were performed. Titles and abstracts were screened separately by two cardio-oncologists (JHC, WTC). Full texts of potentially eligible records were then assessed separately by JHC and WTC before inclusion into review upon joint agreement. RESULTS: 479 records were identified from 3 databases (MEDLINE=51, EMBASE=408, CENTRAL=13) and 1 registry (Clinicaltrials.gov=7). 460 records were excluded based on title and abstract (including duplicates). 19 full text reports were assessed for eligibility and included in review (basic science/animal study paper 2, Clinicaltrials.gov randomised controlled trial submission 1 (currently recruiting), basic science/animal study conference abstract 5, case report 2, review 3, editorial comment 2, clinical guidelines 1, retrospective/registry-based conference abstract 3). CONCLUSION: Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Discontinuation of trastuzumab however, can lead to worse cancer outcomes. There have been case reports, registry-based, retrospective cohort-based and mechanistic studies suggesting the cardioprotective potential of SGLT2i in cancer therapy-related cardiac dysfunction (CTRCD). Based on these, there is now a call for randomised controlled trials to be performed in this patient cohort to advise guideline-directed therapy for CTRCD, which will in turn also provide detailed safety information and improve cancer and cardiovascular outcomes.

International Classification of Functioning, Disability, and Health-based rehabilitation program promotes activity and participation of post-stroke patients.

Background: The International Classification of Functioning, Disability, and Health (ICF) model has been applied in post-stroke rehabilitation, yet limited studies explored its clinical application on enhancing patients' Activity and Participation (ICF-A&P) level. Purpose: This study gathered evidence of the effects of an ICF-based post-stroke rehabilitation program (ICF-PSRP) in enhancing community reintegration in terms of ICF-A&P of post-stroke patients. Methods: Fifty-two post-stroke patients completed an 8 to 12 weeks multidisciplinary ICF-PSRP after setting personal treatment goals in an outpatient community rehabilitation center. Intake and pre-discharge assessments were administered for primary outcomes of Body function (ICF-BF; e.g., muscle strength) and ICF-A&P (e.g., mobility), and secondary outcomes of perceived improvements in ability (e.g., goal attainment and quality of life). Results: There were significantly higher levels in the ICF-BF and ICF-A&P domains, except cognitive function under the ICF-BF. Improvements in the primary outcomes predicted corresponding secondary outcomes. Firstly, expressive and receptive functions (ICP-BF) were mediated by the everyday language (ICF-A&P) which predicted patients' satisfaction with the language-related quality of life. Secondly, upper extremity function (ICP-BF) was mediated by the lower extremity mobility (ICF-A&P) predicting work and productivity-related quality of life. Content analyses showed that combined ICF-BF and ICF-A&P contents throughout the ICF-PSRP contributed to the positive treatment effects. Conclusion: The ICF-PSRP was effective in promoting body function, and activity and participation levels of post-stroke patients. Positive treatment effects are characterized by goal-setting process, cross-domain content design, and community-setting delivery.Clinical trial registration: https://clinicaltrials.gov/study/NCT05941078?id=NCT05941078&rank=1, identifier NCT05941078.

Goal-setting and personalization under the International Classification of Functioning, Disability, and Health framework: Community reintegration program for post-stroke patients.

Background: Body functions and structures, activities, and participation are the core components in the International Classification of Functioning, Disability, and Health (ICF) to identify post-stroke patients' health conditions. The specification of health conditions enhances the outcomes of post-stroke rehabilitation. Purpose: This study aimed to explore the extent and the processes in an ICF-based post-stroke rehabilitation program (ICF-PSRP) that could enhance patients' community reintegration level. Methods: Post-stroke patients who completed the ICF-PSRP participated in intake and pre-discharge individual face-to-face semi-structured interviews. In addition, case therapists were invited to a face-to-face semi-structured group interview. Clinician experts were invited to complete an interview with the same interview contents as case therapists but in an online format. All interview recordings were analyzed with the Framework analysis. Patients' treatment goals were mapped with the ICF Core Set for Stroke. Results: Out of 37 invited post-stroke patients, thirty-three of them completed the interview. Three case therapists and five clinicians completed the interviews. The goals set by the patients and their caregivers showed a broadening of their scope over the course of the program. The changes in scope ranged from the activities to the participation and environmental components. Increases in patient-therapist interactions played an essential role in the goal-setting process, which were integral to personalizing the treatment content. These characteristics were perceived by all parties who contributed to the program outcomes. Conclusion: The application of ICF's principles and core components offers a useful framework for enhancing post-stroke patients' community reintegration level. Future studies should explore the way in which patient-therapist interaction, exposure to environmental factors, and personalized interventions maximize the benefits of applying this framework to the community integration of post-stroke patients.

Diazoxide-unresponsive Hyperinsulinemic Hypoglycaemia in a Preterm Infant with Heterozygous Insulin Receptor Gene Mutation.

Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and Rabson-Mendenhall syndrome, conditions which are associated with significant morbidity early in life. On the other hand, heterozygous INSR gene mutations result in milder phenotype known as type A insulin resistance syndrome. While presentation in adults with this condition is well reported, phenotypes in infant are less well-characterized. We herein report an infant presenting with hyperinsulinemic hypoglycaemia who did not respond to diazoxide therapy. She was subsequently found to carry heterozygous INSR gene mutation. Our patient was a female infant born at 29 weeks of gestation who developed recurrent hypoglycaemia in early infancy. Workup showed hyperinsulinism and she was started on first-line therapy with diazoxide and high-calorie feeds. However, continuous blood glucose monitoring showed post-prandial hyperglycaemia followed by rapid fall to hypogylcaemia. Whole exome sequencing was performed to investigate for diazoxide-unresponsive hyperinsulinism, which revealed a likely pathogenic mutation in the INSR gene c.1246C>T p. (R416X). This nonsense mutation was inherited from the father. With the molecular diagnosis, diazoxide was stopped and she followed a diet with low glycaemic-index food. Subsequent monitoring showed stable glucose profile. Our case highlights the importance to consider type A insulin resistance syndrome when no mutation could be identified in the ABCC8/KCNJ11 genes in diazoxide-unresponsive hyperinsulinism. With autosomal dominant inheritance, cascade screening should be performed in family members to identify those harbouring the mutation as they are at risk of early onset diabetes.

Cross-Ancestry Genome-Wide Association Study Defines the Extended CYP2D6 Locus as the Principal Genetic Determinant of Endoxifen Plasma Concentrations.

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability.

An Effective Test (EOmciSS) for Screening Older Adults With Mild Cognitive Impairment in a Community Setting: Development and Validation Study.

BACKGROUND: Early detection of mild cognitive impairment (MCI) symptoms is an important step to its diagnosis and intervention. We developed a new screening test called "Efficient Online MCI Screening System" (EOmciSS) for use in community-dwelling older adults. It is a self-paced cognitive test to be completed within 10 minutes on tablets or smartphones in homes or care centers for older adults. OBJECTIVE: This study aims to test the validity of EOmciSS for identifying community-dwelling older adults with MCI risks. METHODS: Participants (N=827) completed EOmciSS and other screening tests for MCI. The psychometric properties tested were "subscale item difficulty," "discriminative index," "internal consistency," and "construct validity." We also tested between-group discrimination using the cross-validation method in an MCI group and a normal cognitive function (NCF) group. RESULTS: A total of 3 accuracy factors and 1 reaction time factor explained the structure of the 20 item factors. The difficulty level of accuracy factors (ie, "trail making," "clock drawing," "cube copying," "delayed recall") was 0.63-0.99, whereas that of the reaction time factor was 0.77-0.95. The discriminative index of the medium-to-high-difficulty item factors was 0.39-0.97. The internal consistency (Cronbach α) ranged from .41 (for few item factors) to .96. The training data set contained 9 item factors (CC-Acc1, P<.001; CD-Acc1, P=.07; CD-Acc2, P=.06; CD-Acc3, P<.001; TM-Acc4, P=.07; DR-Acc1, P=.03; RS, P=.06; DR-RT1, P=.02; and DR-RT2, P=.05) that were significant predictors for an MCI classification versus NCF classification. Depressive symptoms were identified as significant factors (P<.001) influencing the performance of participants, and were an integral part of our test system. Age (P=.15), number of years of education (P=.18), and proficiency in using an electronic device (P=.39) did not significantly influence the scores nor classification of participants. Application of the MCI/NCF cutoff score (7.90 out of 9.67) to the validation data set yielded an area under the curve of 0.912 (P<.001; 95% CI 0.868-0.955). The sensitivity was 84.9%, specificity was 85.1%, and the Youden index was 0.70. CONCLUSIONS: EOmciSS was valid and reliable for identifying older adults with significant risks of MCI. Our results indicate that EOmciSS has higher sensitivity and specificity than those of the Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment and the Computerized Cognitive Screen. The user interface, online operation, and self-paced format allowed the test system to be operated by older adults or their caregivers in different settings (eg, home or care centers for older adults). Depressive symptoms should be an integral part in future MCI screening systems because they influence the test performance and, hence, MCI risk. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000039411; http://www.chictr.org.cn/showprojen.aspx?proj=62903.

Causal influences of salience/cerebellar networks on dorsal attention network subserved age-related cognitive slowing.

Age-related cognitive slowing is a prominent precursor of cognitive decline. Functional neuroimaging studies found that cognitive processing speed is associated with activation and coupling among frontal, parietal and cerebellar brain networks. However, how the reciprocal influences of inter- and intra-network coupling mediate age-related decline in processing speed remains insufficiently studied. This study examined how inter- and intra-brain network influences mediate age-related slowing. We were interested in the fronto-insular salience network (SN), frontoparietal dorsal attention network (DAN), cerebellar network (CN) and default mode network (DMN). Reaction time (RT) and functional MRI data from 84 participants (aged 18-75) were collected while they were performing the Arrow Task in visual or audial forms. At the subject level, effective connectivities (ECs) were estimated with regression dynamic causal modelling. At the group level, structural equation models (SEMs) were used to model latent speed based on age and the EC mediators. Age was associated with decreased speed and increased inter-network effective connectivity. The CN exerting influence on the DAN (CN → DAN EC) mediated, while the SN → DAN EC suppressed age-related slowing. The DMN and intra-network ECs did not seem to play significant roles in slowing due to ageing. Inter-network connectivity from the CN and SN to the DAN contributes to age-related slowing. The seemingly antagonizing influences of the CN and SN indicate that increased task-related automaticity and decreased effortful control on top-down attention would promote greater speed in older individuals.

Preterm postnatal complications and risk of attention-deficit/hyperactivity disorder.

AIM: To investigate the association between the risk of attention-deficit/hyperactivity disorder (ADHD) and preterm birth and determine how postnatal complications in children born preterm is associated with the risk of ADHD. METHOD: This population-based cohort study used data from the Hong Kong electronic medical records. We followed 359 614 children (48% female; 6-17 years old, mean 11 years 7 months, SD 3 years 2 months) born in public hospitals in Hong Kong from 1st January 2004 to 31st December 2014 and collected medical records and demographic details for mothers and children until 11th November 2020. RESULTS: The risk of ADHD was 4.0% in children born at term and 5.1% in children born preterm. The odds ratio for ADHD was 2.08 (95% confidence interval [CI] 1.64-2.64) for children born extremely preterm, 1.64 (95% CI 1.46-1.85) for children born very preterm, and 1.15 (95% CI 1.08-1.23) for children born late preterm. Among preterm postnatal complications, only early respiratory disease, retinopathy of prematurity (ROP), and intraventricular haemorrhage were significant predictors of ADHD after controlling for preterm birth, other risk factors, and sociodemographic variables. The excess risk of ADHD among children born very preterm or late preterm could be partly explained by respiratory disease. ROP partially mediated the risk of ADHD in children born very preterm. INTERPRETATION: Children born preterm in all subcategories, from extremely preterm to late preterm, have increased risk of ADHD. Early respiratory infection partially mediates the risk of ADHD in children born preterm.

Interventions for Sensory Over-Responsivity in Individuals with Autism Spectrum Disorder: A Narrative Review.

Individuals with autism spectrum disorder (ASD) often exhibit sensory over-responsivity (SOR), which is characterized by an overwhelmingly negative reaction to or avoidance of sensory stimulation. Despite the detrimental effects of SOR on people's personal and social lives, the knowledge of and interventions for the issue remain limited. This paper collates and reviews studies on SOR and information on the potential for effective interventions for people with ASD. This review reveals evidence that SOR has a close relationship with anxiety, depression, insomnia, and family life impairment and an underlying mechanism related to SOR. Four interventions and their theoretical bases in sensory-motor processing are discussed in this paper, namely, physical activity (PA), sensory integration therapy (SIT), mindfulness-based cognitive therapy (MBCT), and cognitive behavioral therapy (CBT). These interventions focus on establishing coping strategies for regulating the emotional response to sensory information, and they have been found to be effective and to have the potential to help children with ASD reduce their SOR behaviors. This paper provides guidance for selecting appropriate interventions and for further investigation of more effective interventions in the future.

Corrigendum: Higher Affinity Antibodies Bind With Lower Hydration and Flexibility in Large Scale Simulations.

[This corrects the article DOI: 10.3389/fimmu.2022.884110.].

Higher Affinity Antibodies Bind With Lower Hydration and Flexibility in Large Scale Simulations.

We have carried out a long-timescale simulation study on crystal structures of nine antibody-antigen pairs, in antigen-bound and antibody-only forms, using molecular dynamics with enhanced sampling and an explicit water model to explore interface conformation and hydration. By combining atomic level simulation and replica exchange to enable full protein flexibility, we find significant numbers of bridging water molecules at the antibody-antigen interface. Additionally, a higher proportion of interactions excluding bulk waters and a lower degree of antigen bound CDR conformational sampling are correlated with higher antibody affinity. The CDR sampling supports enthalpically driven antibody binding, as opposed to entropically driven, in that the difference between antigen bound and unbound conformations do not correlate with affinity. We thus propose that interactions with waters and CDR sampling are aspects of the interface that may moderate antibody-antigen binding, and that explicit hydration and CDR flexibility should be considered to improve antibody affinity prediction and computational design workflows.

Epidemiology and Trends of Infective Meningitis in Neonates and Infants Less than 3 Months Old in Hong Kong.

OBJECTIVES: Meningitis in neonates and young infants leads to significant morbidity and mortality worldwide. This study aimed to investigate pathogens, antibiotic resistance and secular change of incidence in Hong Kong. METHODS: A retrospective search was performed on meningitis in neonates and infants aged <3 months in three Hong Kong public hospitals from 2004 to 2019. Medical charts were reviewed, with focus on the identification and antibiotic resistance of the pathogens. RESULTS: A total of 200 cases of meningitis were identified (67% were bacterial). Group B Streptococcus (GBS) and Escherichia coli (E. coli) were the commonest bacterial pathogens. The annual rates of early-onset GBS meningitis decreased after the implementation of universal GBS screening and intrapartum antibiotic prophylaxis (IAP) in 2012, while that of late-onset GBS meningitis remained similar. A significant portion of E. coli isolates were resistant to ampicillin and/or gentamicin. CONCLUSION: GBS and E. coli were the most common bacteria for meningitis in this age group. The annual rate of bacterial meningitis in Hong Kong has declined in recent years, which has been attributed to the decline in early-onset GBS meningitis due to universal GBS screening and IAP. Antimicrobial-resistant bacterial strains that cause meningitis require further clinical and public health attention.

Neural and Retinal Characteristics in Relation to Working Memory in Older Adults with Mild Cognitive Impairment.

OBJECTIVE: This study investigated the relationship between neural activities and retinal structures associated with working memory (WM) in older adults with mild cognitive impairment (MCI). METHODS: Eleven older adults with MCI and 29 healthy controls (60 to 73 years old) were tested. All participants underwent an event-related potential (ERP) recording while performing the two-back memory task. The Optical coherence tomography angiography (OCT-A) was administered to examine the perfusion and vessel density in the retina. RESULTS: Results showed that WM performance in the MCI group was negatively associated with ERP latencies in central parietal regions (CP6 and CP8) (ps< 0.05). The left nasal vessel and perfusion densities were negatively correlated with the latencies in these two central parietal regions and positively related to WM performance only in the MCI group (ps< 0.05). CONCLUSION: The findings on WM, central parietal brain activity, and left nasal vessel and perfusion densities in the retina help us gain a better understanding of the neural and retinal underpinnings of WM in relation to MCI.

Aerobic exercise impacts the anterior cingulate cortex in adolescents with subthreshold mood syndromes: a randomized controlled trial study.

Aerobic exercise is effective in alleviating mood symptoms while the mechanism is poorly understood. There are limited clinical trials that investigated the effect of exercise on the anterior cingulate cortex (ACC), a key brain region involved in mood regulations, in adolescents with subthreshold mood syndromes. This randomized controlled trial (RCT) of aerobic exercise was undertaken in a middle school in Guangzhou, China. Participants were adolescents aged 12-14 with subthreshold mood syndromes including depressive and manic symptoms and were randomly assigned to an aerobic exercise intervention or a psychoeducation control group. Participants in the exercise group received moderate-intensity exercise intervention, consisting of 30 mins running, 4 days per week for 3 months. The primary outcome in this study was structural changes in the ACC from baseline to post intervention. The trial was registered with ClinicalTrial.gov (NCT03300778). Of 56 participants who met the criteria for subthreshold mood syndromes, 39 (41.03% males) had complete MRI data, with 20 and 19 subjects in the exercise and control group, respectively. At baseline, demographic information (e.g., age and sex), clinical symptoms, and the gray matter volume and cortical thickness of ACC were matched between the two groups. After 12 weeks of treatment, participants in the exercise group displayed increased gray matter volume of the left rostral ACC (F1,30 = 5.73, p = 0.02) and increased cortical thickness of the right rostral ACC (F1,30 = 7.83, p = 0.01) when compared with the control group. No significant differences were found for caudal ACC cortical thickness and gray matter volume. Our data demonstrate that 12-week, moderate-intensity aerobic exercise can induce structural changes in the rostral ACC in adolescents with subthreshold mood syndromes.

Changes in Mortality and Cerebral Palsy in Extremely Low-Birth-Weight Infants in a Tertiary Center in Hong Kong.

Introduction. We retrospectively reviewed a cohort of extremely low-birth-weight (ELBW) babies born at Queen Mary Hospital and explored if there is any time trend in survival and short-term neurodevelopmental outcomes. Methods. We included ELBW infants born at Queen Mary Hospital between 2008 and 2015. The relationships between multiple risk factors with survival and neurodevelopmental outcomes were analyzed by either Cox regression or univariate logistic regression analysis. We also compared this birth-year period with our previous study from 1993 to 2002. Results. Two hundred seventeen ELBW infants were delivered during the study period. There was significantly higher overall survival rate (81.1%) in 2008 to 2015 compared with 71.4% in 1993 to 2002. One hundred forty-three out of 176 (81%) survivors were assessed at a corrected mean age of 18.1 months. A total of 4.2% had cerebral palsy. There were significantly lower rates of cerebral palsy in 2008 to 2015 (4.2%) compared with 1993 to 2002 (13.5%). Conclusions. We showed a temporal improvement in survival and short-term neurodevelopmental outcomes.

Impact of Cryotherapy on Sensory, Motor, and Autonomic Neuropathy in Breast Cancer Patients Receiving Paclitaxel: A Randomized, Controlled Trial.

Introduction: We conducted a randomized controlled trial evaluating the efficacy and tolerability of cryotherapy in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with early breast cancer receiving neo/adjuvant weekly paclitaxel. Methods: Patients were recruited from the National Cancer Centre Singapore and randomized (1:1) to receive either cryotherapy or usual care. Cryotherapy was applied as frozen gloves and socks on all extremities from 15 min before paclitaxel until 15 min post-infusion every cycle. Efficacy was measured by patient-reported outcomes (Patient Neurotoxicity Questionnaire [PNQ] and EORTC QLQ-CIPN20) and electrophysiological assessments. The primary endpoint was PNQ severity at 2 weeks after 12 cycles of weekly paclitaxel. Results: A total of 46 patients were recruited, of which 8 dropped out before paclitaxel treatment, leaving 38 evaluable. There was no significant difference in PNQ severity between cryotherapy and usual care at 2 weeks after paclitaxel treatment (sensory: p = 0.721; motor: p = 1.000). A benefit was observed at 3 months post-paclitaxel based on PNQ (sensory: 14.3 vs. 41.2%, p = 0.078; motor: 0 vs. 29.4%, p = 0.012) and CIPN20 (sensory: ß = -3.6, 95%CI = -10.5-3.4, p = 0.308; motor: ß = -7.3, 95%CI = -14.6-0, p = 0.051). Additionally, cryotherapy subjects have lower CIPN20 autonomic score (ß = -5.84, 95%CI = -11.15 to -0.524, p = 0.031) and higher sympathetic skin response hand amplitudes (ß = 0.544, 95%CI = 0.108-0.98, p = 0.014), suggesting possible autonomic benefits from cryotherapy. Temporary interruption with cryotherapy occurred in 80.9% of the subjects due to cold intolerance. Conclusions: There is insufficient evidence that cryotherapy prevents sensory neuropathy which may be due to the high rates of cryotherapy interruption in this study. The autonomic benefits of cryotherapy should be further investigated with appropriate outcome measures. Clinical Trial Registration: ClinicalTrials.gov: NCT03429972.

Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs.

BACKGROUND: Rapid whole-exome sequencing (rWES) offers the potential for early diagnosis-predicated precision medicine. Previous evidence focused predominantly on infants from the intensive care unit (ICU). This study sought to examine the diagnostic and clinical utility, and the economic impact on clinical management of rWES in patients beyond infancy and ICU setting. METHODS: rWES was performed on a prospective cohort of patients with suspected monogenic disorder referred from territory-wide paediatric ICUs and non-ICUs in Hong Kong urging for rapid genetic diagnosis. All eligible families were invited. We aimed to achieve a rapid turnaround time (TAT) of 14 days. Clinical utility and costs associated with clinical management were assessed in diagnosed cases. Actual quantitative changes in healthcare utilisation were compared with a counterfactual diagnostic trajectory and/or with matched historical control whenever possible. FINDINGS: rWES were offered to 102 families and 32/102 (31%) patients received a molecular diagnosis, with a median TAT of 11 days. Clinical management changed in 28 of 32 diagnosed patients (88%), including but not limited to modifications in treatment, avoidance of surgeries, and informing decisions on redirection of care. Cost analysis was performed in eight patients. rWES was estimated to reduce hospital length of stay by 566 days and decrease healthcare costs by HKD$8,044,250 (GBP£796,460) for these eight patients. The net cost-savings after inclusion of rWES costs were estimated to be HKD$5,325,187 (GBP£527,246). INTERPRETATION: This study replicates the diagnostic capacity and rapid TAT of rWES in predominantly Chinese patients, and demonstrates diagnosis-predicated precision medicine and net healthcare savings. Findings were corroborated by evidence from multinational cohorts, combined as part of a meta-analysis. rWES merits consideration as a first-tier diagnostic tool for patients with urgent needs in the clinical setting. FUNDING: Health and Medical Research Fund, HKU Seed Fund for Basic Research, The Society for the Relief of Disabled Children, and Edward and Yolanda Wong Fund.

Patterns of relapse after neoadjuvant chemotherapy in breast cancer: implications for surveillance in clinical practice.

PURPOSE: This study aimed to identify patterns of relapse after neoadjuvant chemotherapy (NAC) for breast cancer to refine follow-up recommendations. METHODS: Retrospective analysis on 523 breast cancer patients treated with NAC at two public hospitals in Singapore between 2000 and 2014. RESULTS: Majority of patients (71.9%) had locally advanced disease. Median follow-up was 55 months. 5-year recurrence rate was significantly higher in triple negative breast cancer (TNBC) than non-TNBC subtypes (38.4% vs. 29.5%; p = 0.042); 85% of recurrences involved distant sites. Among TNBC and HR (hormone receptor)-/HER2+ subtypes, 97.0% and 95.0% of relapses occurred within 3 years from diagnosis respectively while 10.6% of relapses among HR+ subgroup occurred beyond 5 years. Recurrence risk in high-grade tumours decreased with time. Stage III at diagnosis (hazard ratio = 2.94; p < 0.001), grade 3 tumours (hazard ratio = 2.87; p = 0.018), not achieving pathologic complete response (pCR) (hazard ratio = 8.77; p = 0.003) and not receiving adjuvant radiotherapy (hazard ratio = 3.19; p < 0.001) were independent predictors of inferior recurrence-free survival. Serum CA 15-3 was raised in 49% of patients upon relapse; it correlated with inferior post-relapse survival (median 11 months vs. 22 months; p = 0.019). CONCLUSIONS: While more intensive follow-up during the first 3 years may be required for patients who do not achieve pCR, especially those with TNBC and HR-/HER2+ tumours, the benefit from blood tests such as CA 15-3 appears limited, and the benefit from intensification of surveillance remains to be addressed in prospective studies on high-risk patients.

Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology.